title: Human colonic myofibroblasts promote expansion of CD4+ CD25high Foxp3+ regulatory T cells.
abstract: OBJECTIVE
  Regulatory T (Treg) cells (CD4+ CD25high FoxP3+) regulate mucosal tolerance; their adoptive transfer prevents or reduces symptoms of colitis in mouse models of inflammatory bowel disease. Colonic CD90+ mesenchymal myofibroblasts and fibroblasts (CMFs) are abundant, nonprofessional antigen-presenting cells in the normal human colonic mucosa that suppress proliferation of activated CD4+ effector T cells. We studied CMF suppressive capacity and evaluated the ability of CMF to induce Treg cells.
  
  
  METHODS
  Allogeneic cocultures of CD4+ T cells and CMFs, derived from normal mucosa of patients undergoing colectomy for colon cancer or inflamed colonic tissues from patients with ulcerative colitis or Crohn's disease, were used to assess activation of the Treg cells.
  
  
  RESULTS
  Coculture of normal CMF with resting or naïve CD4+ T cells led to development of cells with a Treg phenotype; it also induced proliferation of a CD25+ CD127- FoxP3+ T cells, which expressed CTLA-4, interleukin-10, and transforming growth factor-β and had suppressive activities. In contrast to dendritic cells, normal CMFs required exogenous interleukin-2 to induce proliferation of naturally occurring Treg cells. Induction of Treg cells by normal CMFs required major histocompatibility complex class II and prostaglandin E2. CMFs from patients with inflammatory bowel diseases had reduced capacity to induce active Treg cells and increased capacity to transiently generate CD4+CD25+/- CD127+ T cells that express low levels of FoxP3.
  
  
  CONCLUSIONS
  CMFs suppress the immune response in normal colon tissue and might therefore help maintain colonic mucosal tolerance. Alterations in CMF-mediated induction of Treg cells might promote pathogenesis of inflammatory bowel diseases.
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555-0655, USA.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Pinchuk
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Beswick
authors.forename: Jamal I
authors.initials: JI
authors.lastname: Saada
authors.forename: Gushyalatha
authors.initials: G
authors.lastname: Boya
authors.forename: David
authors.initials: D
authors.lastname: Schmitt
authors.forename: Gottumukkala S
authors.initials: GS
authors.lastname: Raju
authors.forename: Julia
authors.initials: J
authors.lastname: Brenmoehl
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reyes
authors.forename: Don W
authors.initials: DW
authors.lastname: Powell
mesh_terms: D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003106:Colon / Q000276:immunology*; D003110:Colonic Neoplasms / Q000276:immunology; D015232:Dinoprostone / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D018928:Immunity, Mucosal; D015212:Inflammatory Bowel Diseases / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation; D058628:Myofibroblasts / Q000276:immunology*; D019899:Paracrine Communication; D010641:Phenotype; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D000949:Histocompatibility Antigens Class II; C508609:IL10 protein, human; C508594:IL2 protein, human; C508017:IL2RA protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human; D015232:Dinoprostone